Abstract
Neuronal circuits within the hypothalamus play a critical role in the homeostatic
regulation of body weight. By disrupting the development or function of these circuits,
human monogenic disorders cause hyperphagia (increased food intake), neuroendocrine
abnormalities, impaired sympathetic nervous system activation, and obesity. Some genetic
disorders also cause maladaptive behaviors such as anxiety, autism, emotional lability,
and aggression, highlighting the role of the specific molecules expressed by these
hypothalamic neurons in the regulation of innate behaviors that are essential to survival.
These findings inform understanding of a wide range of clinical disorders and highlight
the challenges associated with targeting these hypothalamic pathways for weight loss
therapy.
Keywords
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References
- The hunger genes: Pathways to obesity.Cell. 2015; 161: 119-132
- Positional cloning of the mouse obese gene and its human homologue [published correction appears in Nature 1995; 374:479].Nature. 1994; 372: 425-432
- Weight-reducing effects of the plasma protein encoded by the obese gene.Science. 1995; 269: 543-546
- Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks.Science. 1995; 269: 546-549
- Effects of the obese gene product on body weight regulation in ob/ob mice.Science. 1995; 269: 540-543
- Role of leptin in the neuroendocrine response to fasting.Nature. 1996; 382: 250-252
- Neural control of energy balance: Translating circuits to therapies.Cell. 2015; 161: 133-145
- Congenital leptin deficiency is associated with severe early-onset obesity in humans.Nature. 1997; 387: 903-908
- A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction.Nature. 1998; 392: 398-401
- Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.N Engl J Med. 2007; 356: 237-247
- Effects of recombinant leptin therapy in a child with congenital leptin deficiency.N Engl J Med. 1999; 341: 879-884
- Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency.J Clin Invest. 2002; 110: 1093-1103
- Leptin regulates striatal regions and human eating behavior.Science. 2007; 317: 1355
- Leptin receptor signaling in midbrain dopamine neurons regulates feeding.Neuron. 2006; 51: 801-810
- The drive to eat: Comparisons and distinctions between mechanisms of food reward and drug addiction.Nat Neurosci. 2012; 15: 1330-1335
- Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans.Nat Genet. 1998; 19: 155-157
- Obesity due to proopiomelanocortin deficiency: Three new cases and treatment trials with thyroid hormone and ACTH4-10.J Clin Endocrinol Metab. 2003; 88: 4633-4640
- Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene.Nat Genet. 1997; 16: 303-306
- Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist.N Engl J Med. 2016; 375: 240-246
- MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency.Nat Med. 2018; 24: 551-555
- Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: Single-arm, open-label, multicentre, phase 3 trials.Lancet Diabetes Endocrinol. 2020; 8: 960-970
- Targeted disruption of the melanocortin-4 receptor results in obesity in mice.Cell. 1997; 88: 131-141
- Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.N Engl J Med. 2003; 348: 1085-1095
- Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees.Diabetes. 2008; 57: 2511-2518
- Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort.Nat Med. 2021; 27: 1088-1096
- Melanocortin 4 receptor mutations in a large cohort of severely obese adults: Prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating.J Clin Endocrinol Metab. 2006; 91: 1811-1818
- Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation.Cell Rep. 2021; 34: 108862
- Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion.J Clin Endocrinol Metab. 2011; 96: E181-E188
- Evaluation of a melanocortin-4 receptor (MC4R) agonist (setmelanotide) in MC4R deficiency.Mol Metab. 2017; 6: 1321-1329
- Rare variants in single-minded 1 (SIM1) are associated with severe obesity [published correction appears in J Clin Invest 2013; 123:3635].J Clin Invest. 2013; 123: 3042-3050
- Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.J Clin Invest. 2013; 123: 3037-3041
- Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice.Mol Endocrinol. 2008; 22: 1723-1734
- Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader-Willi syndrome: A study of five cases.J Clin Endocrinol Metab. 1995; 80: 573-579
- A transcriptomic signature of the hypothalamic response to fasting and BDNF deficiency in Prader-Willi syndrome.Cell Rep. 2018; 22: 3401-3408
- Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety.Mol Metab. 2017; 6: 1419-1428
- Neurotrophin regulation of neural circuit development and function.Nat Rev Neurosci. 2013; 14: 7-23
- Examination of behavioral deficits triggered by targeting Bdnf in fetal or postnatal brains of mice.Neuroscience. 2006; 142: 49-58
- BDNF-restricted knockout mice as an animal model for aggression.Genes Brain Behav. 2011; 10: 365-374
- Neurotrophins and the regulation of energy balance and body weight.Handb Exp Pharmacol. 2014; 220: 283-307
- Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene.Diabetes. 2006; 55: 3366-3371
- A de novo mutation affecting human TrkB associated with severe obesity and developmental delay.Nat Neurosci. 2004; 7: 1187-1189
- Human BDNF/TrkB variants impair hippocampal synaptogenesis and associate with neurobehavioural abnormalities.Sci Rep. 2020; 10: 9028
- In silico analysis of the V66M variant of human BDNF in psychiatric disorders: An approach to precision medicine.PLoS One. 2019; 14e0215508
- Large, rare chromosomal deletions associated with severe early-onset obesity.Nature. 2010; 463: 666-670
- Human SH2B1 mutations are associated with maladaptive behaviors and obesity [published correction appears in J Clin Invest 2013; 123:526].J Clin Invest. 2012; 122: 4732-4736
- Crucial role of the SH2B1 PH domain for the control of energy balance.Diabetes. 2019; 68: 2049-2062
- Neural deletion of Sh2b1 results in brain growth retardation and reactive aggression.FASEB J. 2018; 32: 1830-1840
- Human gain-of-function MC4R variants show signalling bias and protect against obesity.Cell. 2019; 177: 597-607.e9
- The paraventricular thalamus controls a central amygdala fear circuit.Nature. 2015; 519: 455-459
Article Info
Publication History
Published online: February 04, 2022
Accepted:
January 30,
2022
Received in revised form:
January 11,
2022
Received:
October 8,
2021
Identification
Copyright
© 2022 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
